Chronic Alcohol, Dementia, and CNS Fluid Homeostasis

慢性酒精、痴呆和中枢神经系统液体稳态

• 批准号: 10706469
• 负责人: Helene D Benveniste
• 金额: $ 49.68万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706469
• 关键词: ATP phosphohydrolase; Acceleration; Affect; Alcohol abuse; Alcoholic beverage heavy drinker; Alcohols; Amyloid; Amyloid beta-Protein; Angiography; Angiotensins; Biochemical; Biochemical Pathway; Biophysics; Brain; Calcium Signaling; Central Nervous System; Cerebral Amyloid Angiopathy; Cerebral Ventricles; Cerebrovascular system; Cerebrum; Cessation of life; Chronic; Cognition; Consumption; Dementia; Deposition; Development; Drainage procedure; Elderly; Ethanol; Fluid Balance; Goals; Harvest; Human; Image; Impaired cognition; Inflammation; Inflammatory; Ion Transport; Knowledge; Lateral; Learning; Life; Liquid substance; Literature; Lymph; Lymphatic; Lymphatic System; Magnetic Resonance Imaging; Maps; Measures; Mediator; Meningeal lymphatic system; Meninges; Methods; Modeling; Molecular; Nerve Degeneration; Neuroglia; Neuroimmune; Neurons; Output; Pathology; Pathway interactions; Pattern; Peptides; Perfusion; Persons; Process; Proteins; Proteomics; Protons; Rattus; Regulation; Relapse; Renin; Sampling; Series; Signal Transduction; Stream; Stress; Structure of choroid plexus; Support System; Testing; Therapeutic; Tissues; Toxic effect; Toxin; Up-Regulation; Ventricular; Waste Products; Woman; alcohol effect; alcohol use disorder; arterial spin labeling; blood perfusion; brain tissue; burden of illness; carbonate dehydratase; contrast enhanced; design; drinking; experimental study; fluid flow; glymphatic function; glymphatic system; improved; lymphatic circulation; lymphatic drainage; lymphatic dysfunction; middle age; morphometry; neurotoxicity; normal aging; novel; prevent; protein function; vascular cognitive impairment and dementia; voltage; wasting; white matter

Project Summary/Abstract Alcohol use disorder (AUD) in mid-life is a significant, independent predictor of late-life dementia, particularly vascular cognitive impairment and dementia (VCID) that includes the common subtype cerebral amyloid angiopathy (CAA) characterized by deposits of amyloid-β (Aβ) in the cerebral vasculature. In only one decade, from 2005-2014, the rate of alcohol binging among the elderly rose 20% overall and by 50% in women only. The mechanisms underlying alcohol’s toxic effects on the central nervous system (CNS) remain incompletely understood, which limits the development of strategies targeted to reduce or prevent disease burden in heavy drinkers with and without CAA VCID. An underlying cause of alcohol’s damaging effects on the CNS is a poorly understood dysregulation of CNS fluid homeostasis. Preliminary evidence indicates that alcohol-associated abnormal fluid homeostasis manifests as enlarged cerebral ventricles and altered CSF flow dynamics. In humans, specifically, this manifests as lateral ventricular enlargement, and may reflect not only tissue loss but also itself be contributing to tissue damage and cognitive impairment. We propose that ethanol disrupts fundamentals of fluid homeostasis, by reducing CSF flow through the interconnected glymphatic and lymphatic systems, through biochemical and neuroimmune alterations thereby directly damaging the tissue. The functioning of glymphatic/lymphatic system supports fluid homeostasis and clears waste and toxins from the brain. Our proposed studies include a comprehensive series of experiments to quantitatively analyze alcohol’s effects on CSF secretion, glymphatic and lymphatic transport, and CSF/lymph ‘omics’ profiling in normal brain and with CAA VCID pathology. In Aim 1, we will determine how cEtoh interferes with CSF secretion in rats with/without VCID, using a novel MRI acquisition method to measure choroidal CSF secretion, as well as blood perfusion of the choroid plexus and cortex. We will also implement MRI sequences to measure brain morphometry in cEtoh-exposed rats with/without VCID and sample CSF, the meninges, and brain tissue to study pathology and biochemical lymphatic and inflammatory factors. In Aim 2, we will assess how cEtoh affects glymphatic-lymphatic transport, cerebral and meningeal lymphatic pathology, lymphatic waste output and cognition in rats with/without VCID. We will use dynamic contrast-enhanced MRI and computational fluid dynamics to measure CSF flow dynamics, glymphatic transport, and lymphatic waste drainage as affected by cEtoh and VCID, as well on CAA pathology and cognitive decline. In Aim 3 we will study how cEtoh compromises biochemical signaling and bio-physical changes in the CSF and lymph, including proteins that regulate fluid volume (renin-angiotensin) and proteins functioning in ion transport/signaling (Voltage dependent calcium signal, V-type proton ATPase and Carbonic Anhydrase). Molecular pathways that we identify can later be probed for therapeutic benefit.

项目概要/摘要 中年酒精使用障碍 (AUD) 是晚年痴呆症的重要、独立预测因子，尤其是 血管性认知障碍和痴呆 (VCID)，包括常见的脑淀粉样蛋白亚型 血管病（CAA），其特征是脑血管系统中淀粉样蛋白-β（Aβ）的沉积。仅仅十年的时间， 从2005年到2014年，老年人酗酒的比例总体上升了20%，仅女性就上升了50%。这 酒精对中枢神经系统（CNS）产生毒性作用的机制仍不完全 理解，这限制了旨在减少或预防重度疾病负担的战略的制定 有或没有 CAA VCID 的饮酒者。酒精对中枢神经系统造成损害的一个根本原因是 了解中枢神经系统液体稳态失调。初步证据表明，与酒精相关的 液体稳态异常表现为脑室扩大和脑脊液流动动力学改变。在 特别是人类，这表现为侧脑室扩大，可能不仅反映了组织损失，还反映了 其本身也会导致组织损伤和认知障碍。我们建议乙醇破坏 通过减少脑脊液流经相互连接的类淋巴管和淋巴管来实现液体稳态的基本原理 系统，通过生化和神经免疫改变，从而直接损害组织。这 类淋巴系统的功能支持体液稳态并清除体内的废物和毒素 脑。我们提出的研究包括一系列全面的实验来定量分析酒精的 对正常大脑中脑脊液分泌、类淋巴和淋巴运输以及脑脊液/淋巴“组学”分析的影响 并具有 CAA VCID 病理学。在目标 1 中，我们将确定 cEtoh 如何干扰大鼠脑脊液分泌 有/无 VCID，使用新型 MRI 采集方法测量脉络膜 CSF 分泌以及血液 脉络丛和皮质的灌注。我们还将实施 MRI 序列来测量大脑 对暴露于 cEtoh 的大鼠（有/无 VCID）进行形态测定，并采集 CSF、脑膜和脑组织样本进行研究 病理学和生化淋巴和炎症因子。在目标 2 中，我们将评估 cEtoh 如何影响 淋巴-淋巴运输、脑和脑膜淋巴病理学、淋巴废物输出和 有/没有 VCID 的大鼠的认知。我们将使用动态对比增强 MRI 和计算流体 动态测量脑脊液流动动态、类淋巴运输和淋巴废物排出受以下因素的影响 cEtoh 和 VCID，以及 CAA 病理学和认知能力下降。在目标 3 中，我们将研究 cEtoh 如何妥协 脑脊液和淋巴液中的生化信号传导和生物物理变化，包括调节液体的蛋白质 体积（肾素-血管紧张素）和在离子转运/信号传导中发挥作用的蛋白质（电压依赖性钙信号， V型质子ATP酶和碳酸酐酶）。我们识别出的分子途径可以在以后进行探索 治疗益处。